Highlights of clinical studies during the last year are: 1. The alpha2 antagonist, idazoxan, has produced antidepressant effects only in bipolar and not in unipolar patients. Despite preclinical studies implicating a major role of brain alpha2 receptors in level of alertness relevant to sedation and learning, chronic idazoxan in healthy volunteers did not alter sedative and cognitive responses to alprazolam nor baseline indices of these parameters. An IND to administer intravenous idazoxan to patients and volunteers has been approved and a Phase I study of a more selective analogue, ethoxy-idazoxan is under way. 2. Biochemical studies on noradrenergic output measures in bipolar patients reveal a consistent relative elevation of the "extraneuronal" forms of norepinephrine and normetanephrine. Since we have shown that both lithium and alpha2-receptor blockade increase extraneuronal norepinephrine, a further link between the biochemistry of manic-depressive illness and drug action is suggested. 3. A completed study of intravenous adinazolam and its active metabolite, n-desmethyl adinazolam reveals differential effects of parent compound and metabolite on behavioral (sedation and cognitive impairment) and biochemical (ACTH and cortisol suppresion).